The stimulus-secretion coupling of glucose-induced insulin release: Fuel metabolism in islets deprived of exogenous nutrient

Malaisse, Willy; Best, Leonard; Kawazu, Shoji; Malaisse‐Lagae, Francine; Sener, Abdullah

doi:10.1016/0003-9861(83)90193-5

Cited by 90 publications

(62 citation statements)

References 23 publications

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“…Fatty acids, not glucose, are believed to be the major endogenous energy source for unstimulated islets [67]. This is consistent with the observations that islets maintain high rates of oxygen consumption in the absence of exogenous fuels but contain little glycogen [68].…”

Section: Nefa Metabolism In the Beta Cellsupporting

confidence: 80%

Fatty acid metabolism and insulin secretion in pancreatic beta cells

2003

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Increases in glucose or fatty acids affect metabolism via changes in long-chain acyl-CoA formation and chronically elevated fatty acids increase total cellular CoA. Understanding the response of pancreatic beta cells to increased amounts of fuel and the role that altered insulin secretion plays in the development and maintenance of obesity and Type 2 diabetes is important. Data indicate that the activated form of fatty acids acts as an effector molecule in stimulus-secretion coupling. Glucose increases cytosolic long-chain acylCoA because it increases the "switch" compound malonyl-CoA that blocks mitochondrial β-oxidation, thus implementing a shift from fatty acid to glucose oxidation. We present arguments in support of the following: (i) A source of fatty acid either exogenous or endogenous (derived by lipolysis of triglyceride) is necessary to support normal insulin secretion; (ii) a rapid increase of fatty acids potentiates glucose-stimulated secretion by increasing fatty acyl-CoA or complex lipid concentrations that act distally by modulating key enzymes such as protein kinase C or the exocytotic machinery; (iii) a chronic increase of fatty acids enhances basal secretion by the same mechanism, but promotes obesity and a diminished response to stimulatory glucose; (iv) agents which raise cAMP act as incretins, at least in part, by stimulating lipolysis via beta-cell hormone-sensitive lipase activation. Furthermore, increased triglyceride stores can give higher rates of lipolysis and thus influence both basal and stimulated insulin secretion. These points highlight the important roles of NEFA, LC-CoA, and their esterified derivatives in affecting insulin secretion in both normal and pathological states. [Diabetologia (2003[Diabetologia ( ) 46:1297[Diabetologia ( -1312

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Section: Nefa Metabolism In the Beta Cellsupporting

confidence: 80%

Fatty acid metabolism and insulin secretion in pancreatic beta cells

2003

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“…Inhibition of ceramide formation from palmitate has been shown to reduce FFA toxicity (Lupi et al, 2002). FFA serve as an important source of energy through their mitochondrial β-oxidation (Berne, 1975;Malaisse et al, 1983). Excess FFA are esterified into triglycerides in the ER, and FFA flux into triglycerides augments substantially with increased glucose availability (Briaud et al, 2001;Moffitt et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Initiation and execution of lipotoxic ER stress in pancreatic β-cells

Cunha

Hekerman

Ladrière

et al. 2008

Journal of Cell Science

548

650

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“…It should be mentioned that FFA are the main metabolic substrate of the unstimulated pancreatic b cell 3 and several studies in human and in rodents demonstrate that FFA are essential to maintain insulin secretion during fasting. 4,5 Administration of intralipid and heparin to raise plasma FFA results in an increased GSIS.…”

Section: Short-term Effects Of Fatty Acids On Insulin Secretionmentioning

confidence: 99%

Fat storage in pancreas and in insulin-sensitive tissues in pathogenesis of type 2 diabetes

Assimacopoulos-Jeannet

2004

Int J Obes

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Obesity is associated with increased storage of lipids in nonadipose tissues like skeletal muscle, liver, and pancreatic b cells. These lipids constitute a continuous source of long-chain fatty acyl CoA (LC-CoA) and derived metabolites like diacylglycerol and ceramide, acting as signalling molecules on protein kinases activities (in particular, the family of PKCs), ion channel, gene expression, and protein acylation. In skeletal muscle, the increase in LC-CoA and diacylglycerol translocates and activates specific protein kinase C (PKC) isoforms, which will phosphorylate IRS-1 on serine, preventing its phosphorylation on tyrosine and association with PI3 kinase. This interrupts the insulin signalling pathway leading to the stimulation of glucose transport. In pancreatic b cells, short-term excess of fatty acids or LC-CoA activates PKC and also directly stimulates insulin exocytosis. Longterm exposure to free fatty acids (FFA) leads to an increased basal and blunted glucose-stimulated insulin secretion by affecting gene expression, increase in K ATP channel activity, and uncoupling of the mitochondria. In addition, the saturated FFA palmitate increases cell death by apoptosis via increase in ceramide synthesis.

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The stimulus-secretion coupling of glucose-induced insulin release: Fuel metabolism in islets deprived of exogenous nutrient

Cited by 90 publications

References 23 publications

Fatty acid metabolism and insulin secretion in pancreatic beta cells

Fatty acid metabolism and insulin secretion in pancreatic beta cells

Initiation and execution of lipotoxic ER stress in pancreatic β-cells

Fat storage in pancreas and in insulin-sensitive tissues in pathogenesis of type 2 diabetes

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